The mechanisms of drug and hormone action are being investigated in I strain mice which carry a single gene, sex-linked mutation that results in a marked deficiency in phosphorylase kinase activity to less than 5 percent of that in extracts of comparable muscles of a control strain in mice, C57BL. Yet epinephrine and isoproterenol stimulate glycogenolysis in isolated hemidiaphragms of this pharmacogenetic variant, but with a concentration dependence that differs from that of C57BL. However, the concentration-dependence and time course of isoproterenol-stimulated phosphorylase b to a conversion is the same in I and C57Bl diaphragms except that the maximum amount of phosphorylase a formed in I muscle is 30 percent of that in C57BL. The time course and concentration dependence of the isoproterenol-stimulated increase in cyclic AMP content is the same in muscles from mice of the two strains. Thus, the regulation of isoproterenol-stimulated glycogenolysis in I and C57BL hemidiaphragms appears to be similar except for the lower maximal amount of phosphorylase a formation in I muscle. The role of allosteric effectors of phosphorylase activity, 5'AMP, glucose 6-P, ATP, and Pi, in modulating the glycogenolytic response in the two strains is currently under investigation. These studies will be extended to the mechanisms of glycogenolysis in contracting diaphragm preparations from I and C57BL mice. The nature of the phosphorylase kinase deficiency mutation is being further investigated by purification and characterization of the mutant phosphorylase kinase. Minimization of protease activity during the purification procedures is necessary for its isolation. The subunit structure and the binding of substrates and Ca2 ions by the mutant enzyme will be investigated. BIBLIOGRAPHIC REFERENCES: S.R. Gross, S.E. Mayer, and M.A. Longshore, Stimulation of glycogenolysis by beta-adrenergic agonists in skeletal muscle of mice with the phosphorylase kinase deficiency mutation (I strain), J. Pharm. Exp. Ther. 198:526-538 (1976). S.R. Gross, K.E. Bromwell, and L. DeLateur, Postnatal development of phosphorylase kinase in mouse skeletal muscle, Fed. Proc. 35:854 (1976).